A Systematic Review on the Effectiveness of Antipsychotic Drugs on the Quality of Life of Patients with Schizophrenia

Pharmacological antipsychotic drug interventions represent the cornerstone of the management of patients with schizophrenia and other psychotic spectrum disorders. The choice of the “best” treatment should be made on the basis of several clinical domains. However, despite available treatments, the quality of life reported by patients with schizophrenia taking antipsychotics is still very poor, and this outcome is rarely taken into account in trials assessing the efficacy and effectiveness of antipsychotic treatments. Therefore, we performed a systematic review in order to assess the impact of antipsychotic treatment on patients’ quality of life. In particular, we aimed to identify any differences in the improvement in quality of life according to the (a) type of formulation of antipsychotic drugs (i.e., oral vs. depot vs. long-acting injectable); (b) type of the drug (first vs. second vs. third generation); and (c) patients’ clinical characteristics. One hundred and eleven papers were included in the review. The main findings were as follows: (1) quality of life is usually considered a secondary outcome in trials on the efficacy and effectiveness of drugs; (2) second-generation antipsychotics have a more positive effect on quality of life; and (3) long-acting injectable antipsychotics are associated with a more stable improvement in quality of life and with a good safety and tolerability profile. Our systematic review confirms that quality of life represents a central element for selecting the appropriate treatment for people with schizophrenia. In particular, the availability of new treatments with a better tolerability profile, a proven effectiveness on patients’ cognitive and social functioning, and with a more stable blood concentration might represent the appropriate strategy for improving the quality of life of people with schizophrenia.


Introduction
Schizophrenia is a severe mental disorder, with a prevalence rate of 1 in 300 people (0.32%) worldwide and with approximately 24 million people suffering from this disorder.Schizophrenia is associated with high levels of personal and social burden [1,2].Patients suffering from schizophrenia are at higher risk-compared to the general population-of developing physical comorbidities, including cardiovascular diseases, diabetes, obesity, and cancer, with a significant reduction in life expectancy by 15-20 years [3].Furthermore, patients with schizophrenia often suffer from comorbid mental disorders, including anxiety disorders, with a prevalence rate of 45% [4]; personality disorders, with a prevalence rate of 25% [5]; or substance use disorders, in up to 70% of patients with schizophrenia [6].Low levels of long-term functional recovery have been reported by patients with schizophrenia, with frequent relapses and voluntary/involuntary hospitalizations.In fact, the disorder Brain Sci.2023, 13, 1577 2 of 46 often presents a recurrent course, with relapses and requiring a long-term pharmacological treatment [7,8].Schizophrenia has been conceptualized as a heterogeneous disorder with a complex etiopathogenesis, caused by the interplay between genetic, environmental, and psychosocial factors [9,10].Thus, multilevel, integrated, and personalized treatment is essential for people suffering from schizophrenia [7,11,12].The treatment choice should be made on the basis of several salient clinical domains, such as positive and negative symptom dimensions [13][14][15], other psychopathological components, type of onset and course, neurocognition and social cognition, neurodevelopmental indicators, social functioning, quality of life and unmet needs, clinical staging, antecedent and concomitant psychiatric conditions, physical comorbidities, family history, history of obstetric complications, early and recent environmental exposures, protective factors and resilience, and internalized stigma [16,17].
Remission and recovery rates in people with schizophrenia are still not satisfactory and several unmet clinical needs are reported, including the persistence of negative and cognitive symptoms, and the high relapse and mortality rates in those patients [18,19].Due to the persistence of residual symptoms, patients' functioning can be persistently impaired, affecting the achievement of full-functional recovery [20].
The treatment plan includes both pharmacological and non-pharmacological interventions, usually proposed to the patient according to a sequential process [21][22][23].In particular, pharmacological drug interventions represent the cornerstone in the management of schizophrenia and other psychotic spectrum disorders [24][25][26].People treated with antipsychotics reported a lower mortality rate [3,27] compared to non-treated patients.
However, the levels of quality of life reported by patients taking antipsychotics are still very poor [28,29], and this outcome is rarely taken into account in trials assessing the efficacy and effectiveness of antipsychotic treatments [30].In particular, patients' quality of life is mainly influenced by the persistence of specific symptom domains, such as negative symptoms [31], and by the presence of physical comorbidities [32,33].Therefore, evaluating the impact of antipsychotic treatment on quality of life is essential in order to achieve patients' full recovery.
We performed a systematic review of the available literature in order to assess the impact of antipsychotic treatment on the levels of quality of life.In particular, we aimed to identify any differences in the improvement in quality of life according to the (a) type of formulation of antipsychotic drugs (i.e., oral vs. depot vs. long-acting injectable); (b) type of the drug (first vs. second vs. third generation); and (c) patients' clinical characteristics.

Materials and Methods
This review was performed in five stages: definition of the problem, literature search, data evaluation, data analysis, and presentation of findings.The identification of the research question was performed by using the PICO (patients, intervention, comparison, outcome) framework.In particular, studies including adult (aged 18 or more) inpatients or outpatients with schizophrenia or psychotic disorders, treated with antipsychotic medication, and providing data on quality of life, personal functioning, and/or satisfaction with antipsychotic treatments were included in the review.The search terms "(antipsychotic agents [MeSH] OR antipsychotic drugs OR antipsychotic medications OR neuroleptic drugs OR antipsychotics OR neuroleptics OR long-acting injectable) AND (quality of life [MeSH] OR life quality health-related quality of life OR HRQoL)" were entered into ERIC, MEDLINE, WebofScience, PsycARTICLES, PsycINFO, SCOPUS, and PUBMED (Figure 1).Terms and databases were combined using the Boolean search technique, which consists of a logical information retrieval system (two or more terms combined to make searches more restrictive or detailed).
tions.Similarly, studies reporting only a hypothesis without original data obtained from quality-of-life measures were not considered eligible.Studies on underage children and/or adolescents were excluded since quality of life was assessed using different tools.Grey literature was considered, if sufficient information was provided.
The review process was performed in accordance with PRISMA guidelines, and a PRISMA flowchart was included (Figure 1).

Study Selection and Data Extraction
Three independent researchers (MDV, GM, and LG), having a wide expertise in the field of psychiatry research, including the preparation of systematic reviews, performed literature search, title-abstract screening, and full-text screening.References of relevant articles were hand-searched to evaluate further papers of potential interest.The search In this review, case-controls, cohorts, randomized control trials (RCT), as well as retrospective and prospective real-world experience studies were included.Publications were identified by searching electronic databases and the reference lists of selected articles.The search was limited to studies published in English and was conducted starting from inception to 30 April 2023.
Studies in which psychiatric diagnoses were performed according to the current nosographic criteria (DSM-5 or ICD-11, or previous versions according to the period of time when the study was carried out) and in which measures of quality of life (e.g., selfand clinician-administered scales) were clearly used were considered eligible.
Case reports, editorials, letters to the editor, and reviews were excluded.However, the reference lists of reviews were searched in order to identify relevant primary publications.Similarly, studies reporting only a hypothesis without original data obtained from quality-of-life measures were not considered eligible.Studies on underage children and/or adolescents were excluded since quality of life was assessed using different tools.Grey literature was considered, if sufficient information was provided.
The review process was performed in accordance with PRISMA guidelines, and a PRISMA flowchart was included (Figure 1).

Study Selection and Data Extraction
Three independent researchers (MDV, GM, and LG), having a wide expertise in the field of psychiatry research, including the preparation of systematic reviews, performed literature search, title-abstract screening, and full-text screening.References of relevant articles were hand-searched to evaluate further papers of potential interest.The search process was carried out using a double-blind methodology and discrepancies were solved through consensus.A further researcher (GS) was consulted if needed.The independent researchers also performed data extraction from the included papers, by using an ad hoc extraction tool where the following information was collected: author(s) and year, country, study design, setting, study sample, diagnostic assessment, pharmacological treatment, study outcomes, means of quality-of-life assessment, and relevant results concerning quality of life.
Authors screened the articles identified by the searches and then performed a full-text review of those that appeared relevant to the research topic based on titles and abstracts.Disagreements that arose between the reviewers were resolved through discussion, and in the case of continued disagreement, with the assistance of a senior researcher (AF).
Risk of Bias evaluation has been reported as Supplementary Information Tables.

Results
A total of 3304 records were initially identified, and after duplicate removal, 3123 were assessed by reading abstracts.Following this step, 1256 were excluded.Therefore, 1867 full articles were analyzed and 110 were included in the review (Figure 1).
The main findings of the included papers are summarized in Tables 1-5.
A total of 54% of papers (N = 60) assessed the association between oral antipsychotics and quality of life, whereas 31% (N = 34) of papers assessed the association between longacting injection (LAI) and quality of life (Table 2).In 10% of papers (N = 11), no data were available on the specific type of pharmacological agent included in the study [34][35][36][37][38][39][40][41][42][43][44]; in 4% of papers, a combination of oral and LAI treatments was analyzed, while in the remaining papers, a polytherapy was reported [45,46] (Table 4).The sample size of the included studies significantly varied, ranging from seven subjects with a first episode of psychosis in Cervone et al. [47] to 16,091 patients suffering from schizophrenia in Adrianzén et al. [48].
Longitudinal or cross-sectional observational studies as well as randomized controlled trials represent the most common designs.
In 55 studies, patients were recruited in an outpatient setting, while in 31 studies, patients were recruited at both inpatient and outpatient units.In 14 studies, no clear information was given on the setting of recruitment.
The diagnosis was established through the different editions of the Diagnostic and Statistical Manual of Mental Disorders [59][60][61][62] and the International Classification of Disease [63,64], and was confirmed using validated assessment tools, such as the Positive and Negative Syndrome Scale (PANSS) [65], the Brief Psychiatric Rating Scale (BPRS) [66], the Clinical Global Impression (CGI) [67], and the Global Assessment of Functioning [68].
Quality of life was assessed using different validated and reliable tools, including the Quality-of-Life Scale (QLS); the WHO's WHOQOL-BREF; the Short-Form Health Survey-36 (SF-36); and the Short-Form Health Survey-12 (SF-12).The QLS [69] is a semi-structured interview aimed at rating the deficit derived from schizophrenia by exploring social relations, roles at home/work/school, motivation, and daily activities.The WHOQOL-BREF [70] is a 26-item self-reported tool, focusing on the personal perception of quality of life in terms of physical, psychological, social, and environmental aspects.Health-related quality of life is measured by using the self-reported SF-12 [71] and SF-36 [72], which include perceived levels of physical and social limitations, pain, and energy.
The paper by Meltzer et al. [73] was the first study including a specific focus on the association between the use of antipsychotic medications and quality of life in a small sample (N = 38) of patients with a diagnosis of schizophrenia according to the DSM-III-R.
A cohort study by Lorenzo et al. [78] did not detect significant differences at the WHOQOL-BREF total and subscale scores between haloperidol decanoate and paliperidone palmitate (monthly and quarterly injections).Nasrallah et al. [77] did not find any difference in quality of life between paliperidone palmitate and aripiprazole lauroxil.
In the vast majority of studies including an oral antipsychotic, a positive effect on quality of life was found.Only the study by Fervaha et al. [105] found a modest effect of olanzapine, perphenazine, and quetiapine on quality of life and seven other studies [82,91,93,94,100,106,107] found no effect of oral antipsychotics on quality of life.Among second-and third-generation oral antipsychotics, aripiprazole and lurasidone were associated with the highest levels of improvement in quality of life (Table 1).
When patients were treated with clozapine, a significant improvement in QoL at all the assessments was found [52,90].
The majority of studies confirmed a positive effect of depot/long-acting injectable antipsychotics on quality of life, while only six studies [50,78,[108][109][110][111] did not find any positive effect on quality of life (Table 2).In the study by Nasrallah et al. [77], aripiprazole lauroxil and paliperidone palmitate were found to be associated with a stable improvement in quality of life, and to also have a good safety and tolerability profile.
In four studies [112][113][114][115], patients were treated with a combination of oral and depot/LAI formulations.Only the study by Sugawara et al. [115] did not report details on the type of pharmacological agents used, and no effects were found (Table 3).

SCID-IV, PANSS, ESRS, UKU, SF-36
General health perception subscale was significantly higher in the paliperidone palmitate subgroup.No significant differences were observed in the other subscales.PANSS, CGI-S, DAI-10, EQ-5D, SF-12 Patients rated their quality of life and level of functioning as low at study entry and higher by 12 months or endpoint.CGI-S, GAF, EQ-5D, SF-36naïve-30 Naïve patients had an average higher improvement than the non-naïve, statistically significant in the SF-36 (physical and mental domains).Among the non-naïve patients, significant improvements were found in the CGI-S, GAF, PANSS, and EQ-5D VAS mean scores.

Discussion
The present review aims to evaluate the role of antipsychotic medications on the levels of quality of life in patients with schizophrenia spectrum disorders.In particular, quality of life represents a key component of recovery, which is achieved by relatively few subjects with schizophrenia.As recently stated by international guidelines [158], improving and fostering patients' personal and social functioning in the acute phase of treatment, and continuing to support functioning in the maintenance phase, should be among the major goals of the personalized treatment developed for people with schizophrenia.
The main findings of our review include the following: (1) quality of life is usually considered a secondary outcome of trials on the efficacy and effectiveness of drugs; (2) secondand third-generation antipsychotics have a positive effect on quality of life; and (3) longacting injectable antipsychotics are associated with a more stable improvement in quality of life and with a good safety and tolerability profile (Table 6).Table 6.Key messages.
(1) quality of life has been a neglected and overlooked dimension in the management plan of patients with schizophrenia (2) quality of life has been usually considered a secondary outcome of trials on efficacy and effectiveness of drugs (3) second-and third-generation antipsychotics have a relevant impact on quality of life (4) long-acting injectable antipsychotics are associated with a more stable improvement in quality of life and with good safety and tolerability profile Regarding the first finding, quality of life was a secondary endpoint in all included studies.This should be due to the fact that quality of life is a complex construct, which can be defined in many different ways [159].The complexity has also been confirmed by the fact that several assessment tools are used for measuring such dimension.Furthermore, the levels of quality of life are influenced by several contextual and social factors (such as the levels of support from social networks, and the deprivation index in the area in which the patient is living), as well as by clinical variables (such as the severity of cognitive or negative symptoms).Therefore, the boundaries of the construct of "quality of life" should be redefined in order to include this as a primary outcome in efficacy and effectiveness studies.
However, a positive-and quite unexpected-finding is that quality of life has been mentioned among studies' outcomes since 1990, starting with the study by Meltzer et al. [73].This is probably due to the fact that quality of life has always been considered an important aspect of patients' outcome, which has a significant impact on the levels of personal functioning as well as on relapse and hospitalization rates.
When a second-or third-generation antipsychotic is used, the quality of life improves.It is likely that the better tolerability profile of these drugs compared to first-generation antipsychotics is crucial in the assessment of patients' quality of life [160][161][162][163].
Finally, the use of long-acting injectable antipsychotics was associated with a stable improvement in the levels of quality of life.This effect should be due to the several pharmacokinetic advantages introduced by LAI drugs, which allow for a more stable blood concentration of the drug, with lower rates of side-effects and a better long-term compliance with the treatment.
It should be noted that only one study carried out in 90s' analyzed the impact of neuroleptics on the levels of quality of life of patients with schizophrenia.These data confirm that the quality of life for many decades has not been considered as a relevant clinical dimension for the recovery process of patients with schizophrenia, whereas the reduction in the severity of positive symptoms has been prioritized.
The impact of psychotropic medications on levels of quality of life in people with severe mental disorders has been extensively evaluated in samples of patients suffering from bipolar disorder and treated with lithium [164] or with valproic acid [165] or in patients suffering from major depressive disorder [166].To date, the key role of quality of life in the long-term recovery journey has been widely accepted for all patients suffering from severe mental disorders, but it has been more studied in samples of patients with affective disorders.This represents a relevant unmet need in the management plan of patients with schizophrenia, which should be appropriately filled in.Therefore, the results of the present systematic review should be useful to inform further studies evaluating the long-term efficacy and effectiveness of antipsychotic drugs on clinical dimensions, such as quality of life, which has been overlooked and neglected for many years.
Our systematic review has some limitations, which should be acknowledged.Firstly, in more than 50% of studies, patients were recruited in outpatient settings, which might be affected by a less severe type of the disorder.However, it should be considered that quality of life is a multidimensional construct influenced by several clinical, social, and environmental variables and is strongly dependent on the clinical situation of the moment.Moreover, the search strategy has only been limited to studies including adult patients aged over 18 years.This methodological choice was due to the fact that the presentation of schizophrenia and its treatment in late childhood and/or adolescence can have different clinical and psychosocial characteristics, which are usually assessed through specific assessment tools, specifically validated for the young population.Therefore, a further literature search with a specific focus on patients with a childhood/adolescent onset of schizophrenia should be performed, and the results could be useful to support the development of youth mental health services [167][168][169].
Another limitation is related to the heterogeneity of tools adopted for measuring quality of life.Although all included assessment instruments were validated and reliable, they present specific differences in catching the subtle, different components of quality of life.

Conclusions
The present systematic review confirms that quality of life represents a central element for selecting the appropriate treatment for people with schizophrenia.Within the unmet clinical needs that directly impact the quality of life of these patients, the availability of new treatments with a better tolerability profile, a proven effectiveness on patients' cognitive and social functioning, and a more stable blood concentration might represent the appropriate strategies [170].

Table 1 .
Studies focusing oral antipsychotics and quality of life (N = 60).
BACS, CGI, GAF, JSQLS, AIS, DAI-30, DIEPSS Statistically significant improvements were observed in all subscores of the PANSS, the GAF, and the symptoms and side-effects subscales of the JSQLS, the DIEPSS, the AIS, and the prolactine level.

Table 2 .
Studies focused on long-acting antipsychotics and quality of life (N = 33).
IN: inpatients; OUT: outpatients.SCH: schizophrenia; SPH: schizophreniform disorder; SAD: schizoaffective disorder; DD: delusional disorder; BPD: brief psychotic disorder; FEP: First-Episode Psychosis; PD: Psychotic Disorder.QoL: Quality of Life.RCT: randomized controlled trial.Imp QoL: Improvement in quality of life.Diagnostic and Outcome Assessment tools: AIMS: Abnormal Involuntary Movement Scale; ASEX: Arizona Sexual Experience Scale; BPRS: Brief Psychiatric Rating Scale; CDSS: Calgary Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; DSM: Diagnostic and Statistical Manual of Mental Disorders; GAF: Global Assessment of Functioning; HAM-D: Hamilton Rating Scale for Depression; HAS: Hillside Akathisia scale; ICD-10: International Classification of Diseases 10th Revision; IS: Insight Scale; PANSS: Positive and Negative Syndrome Scale; Q-LES-Q: Quality-of-Life Enjoyment and Satisfaction Questionnaire; QLS: Quality-of-Life Scale; SAS: Simpson Angus Scale; SF: Short-Form Health Survey; SIP: Sickness impact profile; SPS: Social Performance Schedule; WCST: Wisconsin Card Sorting Test; WHOQOL: World Health Organization Quality-of-Life assessment.

Table 5 .
Studies focusing on oral and depot/LAI formulation and quality of life (N = 4).